The present invention relates, in a general way, to a (methanesulfonamido)benzofuran derivative, to its method of preparation and to its use as a synthesis intermediate.
More precisely, the subject of the invention is 2-butyl-5-(methanesulfonamido)benzofuran of formula: 
This compound has proved particularly useful as an intermediate product for the final preparation of (aminoalkoxybenzoyl)benzofuran derivatives, in particular of 2-butyl-3-(4-[3-(dibutylamino)propoxy]-benzoyl)-5-(methanesulfonamido)benzofuran commonly called dronedarone and its pharmaceutically acceptable salts.
This (methanesulfonamido)benzofuran derivative and its pharmaceutically acceptable salts have been described in patent EP0471609 as well as its therapeutic applications. In the cardiovascular field, this compound has proved particularly useful especially as an antiarrhythmic agent.
There has been reported in patent EP0471609, mentioned above, a method for preparing 3-[4-(aminoalkoxy)benzoyl]benzofuran or benzo[b]thiophene derivatives by attaching an aminoalkoxybenzoyl chain to a benzofuran or benzo[b]thiophene derivative, according to which method there is first added to the benzofuran or benzo[b]thiophene derivative in question a benzoyl group containing in the para position an oxygen protected with a methyl group, deprotection is carried out in order to regenerate the hydroxyl functional group and finally the desired aminoalkyl chain is introduced.
More specifically, this method when applied to the preparation of dronedarone comprises the sequence of steps below:
a) reaction of 2-butyl-5-nitrobenzofuran with anisoyl chloride in the presence of tin tetrachloride based on the Friedel-Crafts reaction conditions and hydrolysis to form 2-butyl-3-(4-methoxybenzoyl)-5-nitrobenzofuran,
b) demethylation of the compound thus obtained in the presence of 2.25 molar equivalents of aluminum chloride and hydrolysis so as to form 2-butyl-3-(4-hydroxybenzoyl)-5-nitrobenzofuran,
c) condensation of the compound obtained with 1-chloro-3-(dibutylamino)propane in the presence of potassium carbonate, to give 2-butyl-3-(4-[3-(dibutylamino]propoxylbenzoyl)-5-nitrobenzofuran,
d) hydrogenation of the compound thus formed, in the presence of platinum oxide, which gives 5-amino-2-butyl-3-(4-[3-dibutylamino)propoxy]benzoylbenzofuran,
e) reaction of the 5-aminobenzofuran derivative thus obtained with methanesulfonyl chloride in the presence of triethylamine, which gives dronedarone.
However, this method is not without some disadvantages because, in particular, of the use of aluminum chloride. Indeed, the use of this method on an industrial scale causes high discharges of aluminum hydroxide whose treatment, in order to avoid problems of pollution, is found to be expensive. In addition, the use of 2-butyl-3-(4-methoxybenzoyl)-5-nitrobenzofuran should be avoided as far as possible because of its mutagenic properties.
However, the desired compound is produced with a maximum yield of 60% from 2-butyl-5-nitrobenzofuran according to this method comprising a relatively large number of steps since at least five steps are necessary for the final formation of dronedarone.
The search for an industrial method for the preparation of dronedarone or its pharmaceutically acceptable salts using easily accessible and inexpensive synthesis intermediates based on a more direct method than the earlier method and not using aluminum chloride therefore remains of unquestionable interest.
There has been reported in J. Med. Chem. 1984, 27, 1057-1066 a more convergent method for attaching an aminoalkoxybenzoyl chain to a benzo[b]thiophene derivative without an intermediate step of protecting/deprotecting the hydroxyl functional group. However, this method still proposes on page 1064 the use of aluminum chloride in particularly large quantities since it is of the order of 9 molar equivalents.
According to this method, the benzo[b]thiophene derivative in question is condensed, in an organic phase consisting of dichloroethane, with the hydrochloride of the chloride of the aminoalkoxybenzoyl derivative, this being in the presence of aluminum chloride.
After hydrolysis, the hydrochloride of the desired 3-[4-(aminoalkoxy)benzoyl]benzo[b]thiophene is recovered partly from the organic phase and partly from the aqueous phase by three extractions with chloroform and then treated with sodium hydroxide.
In the context of the preparation of the present invention, this method is applied starting with 2-butyl-5-nitrobenzofuran in order to directly prepare 2-butyl-3-(4-[3-(dibutylamino)propoxyl]benzoyl)-5-nitrobenzofuran, this being using the following steps:
treatment of 2-butyl-5-nitrobenzofuran by means of 4-[3-(dibutylamino)propoxy]benzoyl chloride hydrochloride in the presence of 9 molar equivalents of aluminum chloride, this being in an organic phase,
hydrolysis, recovery of 2-butyl-3-(4-[3-(dibutylamino)propoxy]benzoyl)-5-nitrobenzofuran hydrochloride and treatment with sodium hydroxide so as to form the desired 2-butyl-3-(4-[3-(dibutylamino)propoxy]benzoyl)-5-nitrobenzofuran.
However, this method has proved unsuitable at the industrial level because, on the one hand, of the enormous quantity of aluminum hydroxide thus produced and, on the other hand, of the large amount of impurities recovered and, consequently, of the low yield of 2-butyl-3-(4-[3-(dibutylamino)propoxy]-5-nitrobenzofuran (20 to 30%).
However, it has been found, surprisingly, that it is possible, starting with 2-butyl-5-(methanesulfonamido)benzofuran and using appropriate quantities of a Lewis acid in a Friedel-Crafts reaction, to directly obtain dronedarone hydrochloride with excellent yields since they are at least 85%, it being possible for this hydrochloride to be recovered in a remarkably advantageous manner since it is practically entirely found not in the aqueous phase as might have been predicted but in the organic phase used, which avoids the need to carry out several extractions of this same aqueous phase as in the earlier method.
In addition, the 2-butyl-5-(methanesulfonamido)benzofuran may itself be obtained with great ease and high yields, since they are above 75%, from 5-amino-2-butylbenzofuran and even from the precursor of the latter, namely 2-butyl-5-nitrobenzofuran.
2-Butyl-5-(methanesulfonamido)benzofuran is a novel product which can be easily obtained in crystalline form, unlike 2-butyl-5-nitrobenzofuran whose crystalline state may be difficult to obtain. This methanesulfonamido derivative therefore has an undeniable advantage over the nitro derivative in question.
Consequently, the invention relates to 2-butyl-5-(methanesulfonamido)benzofuran as a novel industrial product useful in particular as synthesis intermediate, for example for the preparation of dronedarone or its pharmaceutically acceptable salts.
Thus, according to the invention, 2-butyl-5-(methanesulfonamido)benzofuran is prepared by reacting 5-amino-2-butylbenzofuran with methanesulfonyl chloride or methanesulfonic anhydride, the reaction taking place in the presence of an acid acceptor such as triethylamine or ammonia, giving the desired compound. Generally, the reaction takes place at room temperature and in one or more apolar solvents preferably chosen from halogenated hydrocarbons and ethers such as, for example, methyl tert-butyl ether, tetrahydrofuran, dichloromethane or dichloroethane.
5-Amino-2-butylbenzofuran, for its part, may be prepared by hydrogenating 2-butyl-5-nitrobenzofuran in the presence of an appropriate catalyst, giving the desired compound.
As catalyst, a platinum derivative such as platinum oxide or an ammonium formate/palladized charcoal system is normally used, the hydrogenation taking place at room temperature and optionally under pressure, for example at a pressure of the order of 20 to 30 bar.
This hydrogenation; which is carried out with excellent yields of up 100%, has unquestionable advantages compared with the hydrogenation of 2-butyl-3-(4-[3-(dibutylamino)propoxy]benzoyl)-5-nitrobenzofuran of the earlier method. Indeed, 2-butyl-5-nitrobenzofuran, apart from the nitro group, contains no other functional group which can be modified by this reaction, unlike the 2-butyl-3-(4-[3-(dibutylamino)propoxy]benzoyl)-5-nitrobenzofuran derivative whose hydrogenation can prove difficult because of the by-products formed.
As indicated above, 2-butyl-5-(methanesulfonamido)benzofuran can be used for the preparation of dronedarone.
Thus, according to the invention, dronedarone is prepared by first forming its hydrochloride, that is to say by reacting, in an organic phase, 2-butyl-5-(methanesulfonamido)benzofuran with 4-[3-(dibutylamino)propoxy]benzoyl chloride hydrochloride, this being in the presence of a Lewis acid as catalyst and by hydrolyzing in order to form dronedarone hydrochloride which is recovered from the organic phase.
The reaction, which is performed under Friedel-Crafts reaction conditions, is normally carried out at room temperature and in an organic phase consisting of one or more solvents chosen from halogenated or nonhalogenated hydrocarbons, preferably of the aliphatic, alicyclic or aromatic type. Generally, halogenated, preferably chlorinated, hydrocarbons of the aliphatic, alicyclic or aromatic type, such as for example dichloromethane, dichloroethane or chlorobenzene, are used.
In addition, the Lewis acid may be aluminum chloride, zinc chloride, boron trifluoride, stannic chloride, titanium tetrachloride or preferably ferric chloride. It is also possible to use a mixture of these Lewis acids. This Lewis acid is used at concentrations which do not exceed 5 molar equivalents, in particular in an amount of 2 to 5 molar equivalents. More particularly, this Lewis acid is used at concentrations which do not exceed 4 molar equivalents. Still more particularly, this Lewis acid is used at concentrations which do not exceed 3 molar equivalents, in particular in an amount of 2 to 3 molar equivalents, preferably 2.5 molar equivalents.
Finally, 4-[3-(dibutylamino)propoxy]benzoyl chloride hydrochloride is used at concentrations of the order of 1 to 1.3 molar equivalents.
The dronedarone hydrochloride thus obtained is then converted, after isolation, to dronedarone by treating with a basic agent such as an alkali metal hydroxide, for example sodium hydroxide, an alkali metal carbonate or an alkali metal hydrogen carbonate such as sodium hydrogen carbonate, which gives the desired compound.
According to a preferred embodiment of the invention, dronedarone is prepared without isolating its hydrochloride which is transiently formed, that is to say in the actual medium where this hydrochloride is prepared.
Consequently, according to one variant of the invention, dronedarone is prepared by means of a method according to which, in an organic phase consisting of one or more solvents chosen from halogenated or nonhalogenated hydrocarbons, 2-butyl-5-(methanesulfonamido)benzofuran is reacted with 4-[3-(dibutylamino)propoxy]benzoyl chloride hydrochloride, this being in the presence of a maximum of 5 molar equivalents, in particular of a maximum of 4 molar equivalents, and preferably of a maximum of 3 molar equivalents of a Lewis acid as catalyst, hydrolysis is carried out in order to obtain transiently, and without isolation, dronedarone hydrochloride which is recovered in the organic phase and the hydrochloride formed is treated with a basic agent, giving dronedarone.
According to another aspect of the invention, dronedarone may be obtained using a three-stage method starting with 2-butyl-5-nitrobenzofuran.
Consequently, another subject of the invention relates to the preparation of dronedarone starting with 2-butyl-5-nitrobenzofuran according to a method by which:
a) 2-butyl-5-nitrobenzofuran is hydrogenated in the presence of an appropriate catalyst, to form 5-amino-2-butylbenzofuran,
b) the compound thus obtained is reacted with methanesulfonyl chloride or methanesulfonic anhydride, the reaction taking place in the presence of an acid acceptor, to form 2-butyl-5-(methanesulfonamido)benzofuran,
c) the methanesulfonamido derivative thus obtained is reacted, in an organic phase consisting of one or more solvents chosen from halogenated or nonhalogenated hydrocarbons, with 4-[3-(dibutylamino)propoxy]benzoyl chloride hydrochloride, this being in the presence of a maximum of 5 molar equivalents, in particular of a maximum of 4 molar equivalents and preferably of a maximum of 3 molar equivalents of a Lewis acid as catalyst, hydrolysis is carried out in order to obtain transiently, and without isolation, dronedarone hydrochloride which is recovered in the organic phase and the hydrochloride formed is treated with a basic agent, giving dronedarone.
Subsequently, the dronedarone obtained according to either method or variant of the invention may be treated, if necessary, with an organic or inorganic acid to form a pharmaceutically acceptable salt of this compound.
4-[3-(Dibutylamino)propoxy]benzoyl chloride hydrochloride, for its part, may be prepared according to the succession of steps below:
a) 1-dibutylamino-3-chloropropane is reacted with a C1-C4 alkyl p-hydroxybenzoate, for example methyl p-hydroxybenzoate, this being in the presence of a basic agent such as an alkali metal carbonate, for example potassium carbonate, to give a methyl 4-[3-(dibutylamino)propoxy]benozate,
b) the ester thus obtained is saponified in the presence of an alkali metal hydroxide, for example sodium hydroxide, and then the salt thus formed is treated with hydrochloric acid to give 4-[3-(dibutylamino)propoxy]benzoic acid hydrochloride,
c) the hydrochloride thus formed is treated with a chlorinating agent, for example thionyl chloride, to give the desired compound.
This use of the method of the invention for the preparation of dronedarone has proved superior to the method of patent EP0471609 in particular because of a smaller number of steps, namely three instead of five starting with 2-butyl-5-nitrobenzofuran and a higher overall yield since it is greater than 65%, or even 70%.
Moreover, this method of the invention involves, in each step, benzofuran intermediates of relatively simple structure, and consequently inexpensive, unlike the earlier method which uses in each of its steps benzofuran derivatives of a fairly elaborate structure.